[unreadable] [unreadable] My career goal is to have an independent academic research laboratory that explores the vascular and renal intracellular signaling events which are involved in the development of complications from hypertension and diabetes. The treatment of these diseases and their complications presents a large financial burden on the health care system and a loss in the quality of life for millions of patients. Understanding the molecular basis of the progression of these diseases and complications will provide new treatment options. One signaling pathway which in vitro data suggests may be involved in the adverse consequences of these diseases is the JAK/STAT pathway. We have also recently demonstrated in vivo that activation of the JAK/STAT pathway is involved in the development of protenuria in type I diabetes. However, there are currently no data investigating this pathway and its mechanisms of regulation in hypertension. Therefore, we propose to test the hypothesis that activation of the JAK/STAT pathway in vivo during hypertension contributes to the development of vascular endothelial dysfunction and renal complications as assessed by alterations in glomerular filtrate rate (GFR), renal blood flow and the development of glomerular sclerosis. The goal of these proposed studies is to use an integrative approach combining whole animal physiology with a biochemical analysis of the intracellular signaling mechanisms to elucidate the molecular mechanisms involved in the development of complications. To achieve this goal we are proposing four specific aims. Specific Aim 1: Determine if activation of the JAK2/STAT pathway contributes to the development of hypertension via a vascular or renal tubular effect. Specific Aim 2: Determine whether activation of the JAK/STAT pathway occurs in multiple models of hypertension. Specific Aim 3: Determine the effects of hypertension on the role of the cytosolic protein tyrosine phosphates, SHP-1, SHP-2 and PTP-1B, and suppressors of cytokine signaling (SOCS) that regulate the JAK/STAT pathway. Specific Aim 4: Determine the interaction of the JAK/STAT with other signaling pathways already implicated in hypertension, specifically PKC, PKA, Rho-kinase and PI3-kinase. Understanding the molecular changes that contribute to the development of end-organ damage in disease states is critical to create additional clinical interventions that could be used in conjunction with traditional therapy. [unreadable] [unreadable] [unreadable] [unreadable]